Controlled release and taste masking oral pharmaceutical compositions

ABSTRACT

The invention relates to tablet comprising granules dispersed in at least one hydrophilic compound or matrix. The granules contain an active agent, at least one amphiphilic compound and at least one lipophilic compound. The tablet may include a gastro-resistant film coating.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 15/646,330,filed on Jul. 11, 2017, which is a continuation of application Ser. No.15/369,296, filed on Dec. 5, 2016, now U.S. Pat. No. 10,064,878, whichis a continuation of application Ser. No. 14/308,305, filed on Jun. 18,2014, now U.S. Pat. No. 9,532,954, which is a continuation ofapplication Ser. No. 13/617,138, filed on Sep. 14, 2012, now U.S. Pat.No. 8,784,888, which is a continuation of application Ser. No.13/462,409, filed on May 2, 2012, now U.S. Pat. No. 8,293,273, which isa continuation of Ser. No. 13/249,839, filed on Sep. 30, 2011, nowabandoned, which is a continuation of application Ser. No. 12/210,969,filed on Sep. 15, 2008, which reissued as U.S. Pat. No. RE43,799 fromU.S. Pat. No. 8,029,823, which is a continuation-in-part of applicationSer. No. 10/009,532, filed on Dec. 12, 2001, now U.S. Pat. No.7,431,943, which is the 35 U.S.C. 371 national stage of Internationalapplication PCT/EP00/05356, filed on Jun. 9, 2000, which claimedpriority to Italian applications MI2000A000422 and MI99A001317 filedMar. 3, 2000 and Jun. 14, 1999, respectively. The entire contents ofeach of the above-identified applications are hereby incorporated byreference.

The present invention relates to controlled release and taste-maskingcompositions containing one or more active principles incorporated in athree-component matrix structure, i.e. a structure formed by successiveamphiphilic, lipophilic or inert matrices and finally incorporated ordispersed in hydrophilic matrices. The use of a plurality of systems forthe control of the dissolution of the active ingredient modulates thedissolution rate of the active ingredient in aqueous and/or biologicalfluids, thereby controlling the release kinetics in the gastrointestinaltract, and it also allows the oral administration of active principleshaving unfavourable taste characteristics or irritating action on themucosae of the administration site, particularly in the buccal area.

The compositions of the invention can contain active principlesbelonging to the therapeutical classes of analgesics,antiinflammatories, cardioactives, tranquilizers, antihypertensives,disinfectants and topical antimicrobials, antiparkinson drugs,antihistamines and are suitable to the oral administration or for actingtopically at some areas of the gastrointestinal tract.

TECHNOLOGICAL BACKGROUND

The preparation of a sustained, controlled, delayed or anyhow modifiedrelease form can be carried out according to different known techniques:

-   -   1. The use of inert matrices, in which the main component of the        matrix structure opposes some resistance to the penetration of        the solvent due to the poor affinity towards aqueous fluids;        such property being known as lipophilia.    -   2. The use of hydrophilic matrices, in which the main component        of the matrix structure opposes high resistance to the progress        of the solvent, in that the presence of strongly hydrophilic        groups in its chains, mainly branched, remarkably increases        viscosity inside the hydrated layer.    -   3. The use of bioerodible matrices, which are capable of being        degraded by the enzymes of some biological compartment.

All the procedures listed above suffer, however, from drawbacks andimperfections.

Inert matrices, for example, generally entail non-linear, butexponential, release of the active ingredient.

Hydrophilic matrices have a linear behaviour until a certain fraction ofactive ingredient has been released; then they significantly deviatefrom linear release.

Bioerodible matrices are ideal to carry out the so-called“site-release”, but they involve the problem of finding the suitableenzyme or reactive to degradation. Furthermore, they frequently releasein situ metabolites that are not wholly toxicologically inert.

A number of formulations based on inert lipophilic matrices have beendescribed: Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses aprocess making use of varying amounts of colloidal silica as aporization element for a lipophilic inert matrix in which the activeingredient is incorporated.

The same notion of canalization of an inert matrix is described in U.S.Pat. No. 4,608,248 in which a small amount of a hydrophilic polymer ismixed with the substances forming an inert matrix, in a non sequentialcompenetration of different matrix materials.

EP 375,063 discloses a technique for the preparation of multiparticulategranules for the controlled-release of the active ingredient whichcomprises co-dissolution of polymers or suitable substances to form ainert matrix with the active ingredient and the subsequent deposition ofsaid solution on an inert carrier which acts as the core of the device.Alternatively, the inert carrier is kneaded with the solution containingthe inert polymer and the active ingredient, then the organic solventused for the their dissolution is evaporated off to obtain a solidresidue. The resulting structure is a “reservoir”, i.e. is notmacroscopically homogeneous along all the symmetry axis of the finalform.

The same “reservoir” structure is also described in Chem. Pharm. Bull.46 (3), 531-533, (1998) which improves the application through anannealing technique of the inert polymer layer which is deposited on thesurface of the pellets.

To the “reservoir” structure also belong the products obtained accordingto the technique described in WO 93/00889 which discloses a process forthe preparation of pellets in hydrophilic matrix which comprises:

-   -   dissolution of the active ingredient with gastro-resistant        hydrophilic polymers in organic solvents;    -   drying of said suspension;    -   subsequent kneading and formulation of the pellets in a        hydrophilic or lipophilic matrix without distinction of        effectiveness between the two types of application.

EP 0 453 001 discloses a multiparticulate with “reservoir” structureinserted in a hydrophilic matrix. The basic multiparticulate utilizestwo coating membranes to decrease the release rate of the activeingredient, a pH-dependent membrane with the purpose of gastricprotection and a pH-independent methacrylic membrane with the purpose ofslowing down the penetration of the aqueous fluid.

WO 95/16451 discloses a composition only formed by a hydrophilic matrixcoated with a gastro-resistant film for controlling the dissolution rateof the active ingredient.

When preparing sustained-, controlled-release dosage forms of amedicament topically active in the gastrointestinal tract, it isimportant to ensure a controlled release from the first phases followingadministration, i.e. when the inert matrices have the maximum releaserate inside the logarithmic phase, namely the higher deviation fromlinear release.

Said object has been attained according to the present invention,through the combination of an amphiphilic matrix inside an inert matrix,the latter formulated with a lipophilic polymer in a superficialhydrophilic matrix. The compositions of the invention are characterizedby the absence of a first phase in which the medicament superficiallypresent on the matrix is quickly solubilized, and by the fact theamphiphilic layer compensate the lack of affinity of the aqueous solventwith the lipophilic compounds forming the inner inert matrix.

DISCLOSURE OF THE INVENTION

The invention provides controlled release and taste masking oralpharmaceutical compositions containing an active ingredient, comprising:

-   -   a) a matrix consisting of lipophilic compounds with melting        point lower than 90° C. and optionally by amphiphilic compounds        in which the active ingredient is at least partially        incorporated;    -   b) optionally an amphiphilic matrix;    -   c) an outer hydrophilic matrix in which the lipophilic matrix        and the optional amphiphilic matrix are dispersed;    -   d) optionally other excipients.

A particular aspect of the invention consists of controlled release oralcompositions containing one or more active ingredients comprising:

-   -   a) a matrix consisting of amphiphilic compounds and lipophilic        compounds with melting point below 90° C. in which the active        ingredient is at least partially incorporated;    -   b) an outer hydrophilic matrix in which the        lipophilic/amphiphilic matrix is dispersed;    -   c) optional other excipients.

A further aspect of the invention provides taste masking oralpharmaceutical compositions containing one or more active ingredientscomprising:

-   -   an inert or lipophilic matrix consisting of C6-C20-alcohols or        C8-C20 fatty acids or esters of fatty acids with glycerol or        sorbitol or other polyalcohols with carbon atom chain not higher        than six;    -   an amphiphilic matrix consisting of polar lipids of type I or II        or glycols partially etherified with C1-C4 alkyl chains;    -   an outer hydrophilic matrix containing the above matrices,        mainly formed by saccharide, dextrin, polyalcohol or cellulose        compounds or by hydrogels;    -   optional excipients to give stability to the pharmaceutical        formulation.

DETAILED DISCLOSURE OF THE INVENTION

The compositions of the invention can be prepared by a method comprisingthe following steps:

a) the active ingredient is first inglobated by simple kneading ormixing in a matrix or coating consisting of compounds having amphiphilicproperties, which will be further specified below. The activeprinciple(s) can be mixed with the amphiphilic compounds without the aidof solvents or with small amounts of water-alcoholic solvents.

b) The matrix obtained in a) is incorporated in a low melting lipophilicexcipient or mixture of excipients, while heating to soften and/or meltthe excipient itself, which thereby incorporates the active ingredientby simple dispersion. After cooling at room temperature an inert matrixforms, which can be reduced in size to obtain inert matrix granulescontaining the active ingredient particles.

c) The inert matrix granules are subsequently mixed together with one ormore hydrophilic water-swellable excipients. The mixture is thensubjected to compression or tabletting. This way, when the tablet iscontacted with biological fluids, a high viscosity swollen layer isformed, which coordinates the solvent molecules and acts as a barrier topenetration of the aqueous fluid itself inside the new structure. Saidbarrier antagonizes the starting “burst effect” caused by thedissolution of the medicament inglobated inside the inert matrix, whichis in its turn inside the hydrophilic matrix.

The amphiphilic compounds which can be used according to the inventioncomprise polar lipids of type I or II (lecithin, phosphatidylcholine,phosphatidylethanolamine), ceramides, glycol alkyl ethers such asdiethylene glycol monomethyl ether (Transcutol®).

The lipophilic matrix consists of substances selected from unsaturatedor hydrogenated alcohols or fatty acids, salts, esters or amidesthereof, fatty acids mono-, di- or triglycerides, the polyethoxylatedderivatives thereof, waxes, ceramides, cholesterol derivatives ormixtures thereof having a melting point within the range of 40 to 90°C., preferably from 60 to 70° C.

If desired, a fatty acid calcium salt may be incorporated in thelipophilic matrix which is subsequently dispersed in a hydrophilicmatrix prepared with alginic acid, thus remarkably increasing thehydrophilic matrix viscosity following penetration of the solvent frontuntil contact with the lipophilic matrix granules dispersed inside.

According to an embodiment of the invention, an amphiphilic matrix withhigh content in active ingredient, typically from 5 to 95% w/w, is firstprepared by dispersing the active ingredient or the mixture of activeingredients in a mixture of amphiphilic compounds, such as lecithin,other type II polar lipids, surfactants, or in diethylene glycolmonoethyl ether; the resulting amphiphilic matrix is then mixed orkneaded, usually while hot, with lipophilic compounds suitable to forman inert matrix, such as saturated or unsaturated fatty acids, such aspalmitic, stearic, myristic, lauric, laurylic, or oleic acids ormixtures thereof with other fatty acids with shorter chain, or salts oralcohols or derivatives of the cited fatty acids, such as mono-, di-, ortriglycerides or esters with polyethylene glycols, alone or incombination with waxes, ceramides, cholesterol derivatives or otherapolar lipids in various ratios so that the melting or softening pointsof the lipophilic compounds mixtures is within the range of 40 to 90°C., preferably from 60 to 70° C.

Alternatively, the order of formation of the inert and amphiphilicmatrices can be reversed, incorporating the inert matrix inside theamphiphilic compounds.

The resulting inert lipophilic matrix is reduced into granules by anextrusion and/or granulation process, or any other known processes whichretain the homogeneous dispersion and matrix structure of the startingmixture.

The hydrophilic matrix consists of excipients known as hydrogels, i.e.substances which when passing from the dry state to the hydrated one,undergo the so-called “molecular relaxation”, namely a remarkableincrease in mass and weight following the coordination of a large numberof water molecules by the polar groups present in the polymeric chainsof the excipients themselves.

Examples of hydrogels which can be used according to the invention arecompounds selected from acrylic or methacrylic acid polymers orcopolymers, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkylcelluloses, polysaccharides, dextrins, pectins, starches andderivatives, natural or synthetic gums, alginic acid.

In case of taste-masking formulations, the use of polyalcohols such asxylitol, maltitol and mannitol as hydrophilic compounds can also beadvantageous.

The lipophilic matrix granules containing the active ingredient aremixed with the hydrophilic compounds cited above in a weight ratiotypically ranging from 100:0.5 to 100:50 (lipophilic matrix:hydrophilicmatrix). Part of the active ingredient can optionally be mixed withhydrophilic substances to provide compositions in which the activeingredient is dispersed both in the lipophilic and the hydrophilicmatrix, said compositions being preferably in the form of tablets,capsules and/or minitablets.

The compression of the mixture of lipophilic and/or amphiphilic matrix,hydrogel-forming compound and, optionally, active ingredient notinglobated in the lipophilic matrix, yields a macroscopicallyhomogeneous structure in all its volume, namely a matrix containing adispersion of the lipophilic granules in a hydrophilic matrix. A similarresult can also be obtained by coating the lipophilic matrix granuleswith a hydrophilic polymer coating.

The tablets obtainable according to the invention can optionally besubjected to known coating processes with a gastro-resistant film,consisting of, for example, methacrylic acids polymers (Eudragit®) orcellulose derivatives, such as cellulose acetophthalate.

Active ingredients which can conveniently be formulated according to theinvention comprise:

analgesics, such as acetaminophen, phenacetin, sodium salicylate;antitussives, such as dextromethorphan, codeine phosphate;

bronchodilators, such as albuterol, procaterol;

antipsychotics, such as haloperidol, chlorpromazine;

antihypertensives and coronary-dilators, such as isosorbide mono- anddinitrate, captopril;

selective β2 antagonists such as salbutamol, terbutaline, ephedrine,orciprenaline sulfate;

calcium antagonists, such as nifedipine, nicardipine, diltiazem,verapamil;

antiparkinson drugs, such as pergolide, carpidopa, levodopa;

non steroid anti-inflammatory drugs, such as ketoprofen, ibuprofen,diclofenac, diflunisal, piroxicam, naproxen, ketorolac, nimesulide,thiaprophenic acid, mesalazine (5-aminosalicylic acid); antihistamines,such as terfenedine, loratadine;

antidiarrheals and intestinal antiinflammatories, such as loperamide,5-aminosalicylic, olsalazine, sulfasalazine, budenoside;

spasmolytics such as octylonium bromide;

anxiolytics, such as chlordiazepoxide, oxazepam, medazepam, alprazolam,donazepam, lorazepan;

oral antidiabetics, such as glipizide, metformin, phenformin,gliclazide, glibenclamide;

cathartics, such as bisacodil, sodium picosulfate;

antiepileptics, such as valproate, carbamazepine, phenyloin, gabapentin;

antitumorals, such as flutamide, etoposide;

oral cavity disinfectants or antimicrobials, such as benzalkoniumchloride, cetylpyridinium chloride or tibezonium iodide, and some aminoderivatives such as benzydamine and chlorhexidine as well as the saltsand derivatives thereof;

sodium fluoride.

The compositions of the invention can further contain conventionalexcipients, for example bioadhesive excipients such as chitosans,polyacrylamides, natural or synthetic gums, acrylic acid polymers.

The compositions of the invention can contain more than one activeingredient, each of them being optionally contained in the hydrophilicmatrix or in the inert amphiphilic matrix, and are preferably in theform of tablets, capsules or minitablets.

In terms of dissolution characteristics, contact with water or aqueousfluids causes the immediate penetration of water inside the moresuperficial layer of the matrix which, thanks to the presence of theaqueous solvent, swells due to the distension of the polymeric chains ofthe hydrogels, giving rise to a high viscosity hydrated front whichprevents the further penetration of the solvent itself linearly slowingdown the dissolution process to a well determined point which can belocated at about half the thickness, until the further penetration ofwater would cause the disintegration of the hydrophilic layer andtherefore the release of the content which, consisting of inert matrixgranules, however induces the diffusion mechanism typical of thesestructures and therefore further slows down the dissolution profile ofthe active ingredient.

The presence of the amphiphilic matrix inside the lipophilic matrixinert allows to prevent any unevenness of the release profile of theactive ingredient. The surfactants present in the amphiphilic portionpromote wettability of the porous canaliculuses which cross the inertmatrix preventing or reducing resistance to penetration of the solventinside the inert matrix.

To obtain taste masking tablets, the components of the hydrophilicmatrix are carefully selected to minimize the active substance releasetime through penetration accelerated by the canalization induced by thehydrophilic compound.

The following Examples illustrate the invention in greater detail.

Example 1

500 g of 5-aminosalicylic-acid and 20 g of octylonium bromide are mixedwith 10 g of soy lecithin dissolved in 50 g of a water:ethyl alcohol 1:3mixture at about 50° C. After homogenization and drying, the granules ofthe resulting matrix are treated in a kneader with 20 g of carnauba waxand 50 g of stearic acid, heating until homogeneous dispersion, thencold-extruded into small granules. The inert matrix granules are loadedinto a mixer in which 30 g of carbopol 971 P and 65 g of hydroxypropylmethylcellulose are sequentially added. After a first mixing step forhomogeneously dispersing the powders, 60 g of microcrystalline celluloseand 5 g of magnesium stearate are added. After mixing, the final mixtureis tabletted to unitary weight of 760 mg/tablet. The resulting tabletsare film-coated with cellulose acetophthalate or polymethacrylates and aplasticizer to provide gastric resistance and prevent the early releaseof product in the stomach.

The resulting tablets, when subjected to dissolution test in simulatedenteric juice, have shown a release of the active principles having thefollowing profile: after 60 minutes no more than 30%, after 180 minutesno more than 60%, after 5 hours no more than 80%.

Example 2

50 g of diethylene glycol monoethyl ether are homogeneously distributedon 500 g of microcrystalline cellulose; then 100 g of Budesonide areadded, mixing to complete homogenization. This mix is further added with400 g of Budesonide, then dispersed in a blender containing 100 g ofcarnauba wax and 100 g of stearic acid preheated at a temperature of 60°C. After kneading for 5 minutes, the mixture is cooled to roomtemperature and extruded in granules of size below 1 mm.

A suitable mixer is loaded with the matrix granules prepared as aboveand the following amounts of hydrophilic excipients: 1500 g ofhydroxypropyl methylcellulose and 500 g of policarbophil.

The components are mixed until homogeneous dispersion of the matrices,then added with 2450 g of microcrystalline cellulose, 400 g of lactose,100 g of colloidal silica and 50 g of magnesium stearate. After further5 minute mixing, the mix is tabletted to unitary weight of 250mg/tablet.

Example 3

850 g of metformin are dispersed in a granulator/kneader with 35 g ofdiethylene glycol monoethyl ether previously melted with 100 g ofstearic acid and 55 g of carnauba wax. The system is heated to carry outthe granulation of the active ingredient in the inert matrix. Theresulting 1040 g of formulation are added with 110 g of hydroxypropylmethylcellulose and 20 g of magnesium stearate.

The final mixture is tabletted to unitary weight of 1170 mg/tabletequivalent to 850 mg of active ingredient.

The resulting tablets, when subjected to dissolution test in simulatedenteric juice, have shown a release of the active principles having thefollowing profile: after 60 minutes no more than 35%, after 180 minutesno more than 60%, after 5 hours no more than 80%.

Example 4

120 g of octylonium bromide are dispersed in a granulator/kneader with30 g of stearic acid and 15 g of beeswax in which 10 g of diethyleneglycol monoethylene had previously been melted.

The system is heated to carry out the granulation of the activeingredient in the inert matrix. The resulting 10 g of formulation areadded with 5 g of hydroxypropyl methylcellulose and 5 g ofpolicarbophyl, 2 g of magnesium stearate and 3 g of microcrystallinecellulose.

The final mixture is tabletted to unitary weight of 200 mg/tabletequivalent to 120 mg of active ingredient.

The resulting tablets, when subjected to dissolution test in simulatedenteric juice, have shown a release of the active principles having thefollowing profile: after 60 minutes no more than 25%; after 180 minutesno more than 50%; after 5 hours no more than 70%.

Example 5

12 g of diethylene glycol monoethyl ether are loaded on 6 g ofmicrocrystalline cellulose and 6 grams of calcium carbonate, then 100 gof Gabapentin are added and the mixture is homogenized. After that, 800g of Gabapentin are added which are dispersed in a granulator/kneaderwith 4.5 g of white wax and 5 g of stearic acid. The system is heated tocarry out the granulation of the active ingredient in the inert matrix.The resulting 916.5 g of formulation are added with 39.5 g ofhydroxypropyl methylcellulose, 10 g of alginic acid, 11 g of magnesiumstearate and 6 g of syloid. The final mixture is tabletted to unitaryweight of 1000 mg/tablet equivalent to 900 mg of active ingredient.

Example 6

50 g (25 g) of carbidopa and 200 g (100 g) of levodopa are dispersed ina granulator/kneader with 60 g (30 g) of stearic acid and 30 g (15 g) ofyellow wax, in which 10 (5) g of diethylene glycol monoethyl ether hadpreviously been melted.

The system is heated to carry out the granulation of the activeingredient in the inert matrix. The resulting 340 g (170 g) offormulation are added with 20 g (10 g) of hydroxypropyl methylcellulose,10 g (5 g) of xantan gum, 16 g (8 g) of microcrystalline cellulose, 4 g(2 g) of magnesium stearate.

The final mixture is tabletted to unitary weight of 400 (200) mg/tabletequivalent to 50 (25) mg of carbidopa and 200 (100) mg di levodopa.

Example 7

4 g of Nimesulide are solubilised in 50 g of diethylene glycol monoethylether, then 100 g of microcrystalline cellulose are added to obtain ahomogeneous mixture.

The resulting mixture is added in a granulator/kneader with 196 g ofNimesulide, 50 g of stearic acid and 25 g of carnauba wax. The system isheated to carry out the granulation of the active ingredient in theinert and amphiphilic matrix system.

425 g of the resulting granulate are added with 60 g of hydroxypropylmethylcellulose, 5 g of policarbophil and 10 g of magnesium stearate.

The final mixture is tabletted to unitary weight of 500 mg/tabletequivalent to 200 mg of active ingredient.

The resulting tablets, when subjected to dissolution test in simulatedenteric juice, have shown a release of the active principles having thefollowing profile: after 1 hour no more than 25%, after 2 hours no morethan 40%, after 4 hours no more than 60%, after 8 hours no more than90%.

Example 8

500 g of propionyl carnitine are dispersed in a granulator/kneader with90 g of stearic acid and 40 g of carnauba wax, in which 20 g ofdiethylene glycol monoethyl ether had previously been melted. The systemis heated to carry out the granulation of the active ingredient in theinert/amphiphilic matrix. The resulting 650 g of formulation are addedwith 60 g of hydroxypropyl methylcellulose and 10 g of magnesiumstearate.

The final mixture is tabletted to unitary weight of 720 mg/tabletequivalent to 500 mg of active ingredient.

The resulting tablets, when subjected to dissolution test in simulatedenteric juice, have shown a release of the active principles having thefollowing profile: after 60 minutes no more than 40%, after 180 minutesno more than 60%, after 4 hours no more than 80%, after 8 hours no morethan 90%.

Example 9

One kg of Nimesulide is placed in a high rate granulator, pre-heated toabout 70°, together with 200 g of cetyl alcohol and 25 g of glycerolpalmitostearate the mixture is kneaded for about 15 minutes and stirredwhile decreasing temperature to about 30° C. The resulting inert matrixis added, keeping stirring and kneading during cooling, with 50 g of soylecithin and 50 g of ethylene glycol monoethyl ether. The granulate isextruded through a metallic screen of suitable size and mixed with 50 gof hydroxypropyl methylcellulose, 1320 kg of maltodextrins, 2 kg oflactose-cellulose mixture, 50 g of colloidal silica, 40 g of aspartame,150 g of citric acid, 75 g of flavour and 65 g of magnesium stearate.The final mixture is tabletted to unitary weight of about 500 mg, havinghardness suitable for being dissolved in the mouth and a pleasant taste.

Example 10

Operating as in the preceding example, chewable tablets are preparedreplacing dextrin with mannitol and the lactose-cellulose mixture withxylitol. The resulting tablets have pleasant taste and give upon chewinga sensation of freshness enhancing the flavour.

Example 11

Operating as described in example 9, but with the following components:

active ingredient: ibuprofen mg 100 lipophilic/inert matrix component:mg 15 cetyl alcohol amphiphilic matrix component: soy lecithin mg 8hydrophilic matrix components: mannitol mg 167 maltodextrins mg 150methylhydroxypropylcellulose mg 30 adjuvants: aspartame mg 15 flavour mg5 colloidal silica mg 5 magnesium stearate mg 5

500 mg unitary weight tablets are obtained, which undergo progressiveerosion upon buccal administration, and effectively mask the bitter,irritating taste of the active ingredient.

Example 12

Operating as described in example 9, but with the following components:

active ingredient: diclofenac sodium mg 25 lipophilic/inert matrixcomponent: mg 5 cetyl alcohol glycerol palmitostearate mg 5 amphiphilicmatrix component: mg 7 soy lecithin hydrophilic matrix components:xylitol mg 168 maltodextrins mg 150 hydroxypropylmethylcellulose mg 20adjuvants: aspartame mg 5 flavour mg 5 colloidal silica mg 5 magnesiumstearate mg 5

400 mg unitary weight tablets are obtained, which undergo progressiveerosion upon buccal administration, and effectively mask the irritatingtaste of the active ingredient.

Example 13

Operating as described in example 9, but with the following components:

active ingredient: chlorhexidine mg 2.5 lipophilic/inert matrixcomponent: mg 0.5 cetyl alcohol glycerol palmitostearate mg 0.5amphiphilic matrix component: mg 0.3 diethylene glycol monoethyl etherhydrophilic matrix components: xylitol mg 38 maltodextrins mg 96hydroxypropyl methylcellulose mg 10 adjuvants: aspartame mg 3 flavour mg5 colloidal silica mg 2 magnesium stearate mg 2

150 mg unitary weight tablets are obtained, which undergo progressiveerosion upon buccal administration, and effectively mask the irritatingtaste of the active ingredient.

Example 14

One Kg of Nimesulide is placed in a high rate granulator, pre-heated toabout 70°, together with g 125 of cetyl alcohol: the mixture is kneadedfor about 15 minutes and stirred while decreasing temperature to about30° C., then added with g 30 of lecithin. The resulting matrix is thenextruded through a metallic screen of suitable size and mixed with 2.415kg of lactose, 1.0 kg of maltodextrins, 50 g of hydroxypropylmethylcellulose, 50 g of colloidal silica, 40 g of aspartame, 150 g ofcitric acid, 75 g of flavour and 65 g of magnesium stearate. The finalmixture is tabletted to about 500 mg tablets, having hardness suitablefor being dissolved in the mouth and pleasant taste.

Example A

2.7 kg of budesonide, 3.0 kg of lecithin (amphiphilic matrix formingmaterial) and 3.0 kg of stearic acid (lipophilic matrix formingmaterial) are mixing after sieving till an homogeneous mixture isobtained; then add 39.0 kg of inert, functional excipients and 9.0 kg oflow viscosity hydroxypropylcellulose (binder) and mix for 10 minutesbefore adding purified water and kneading to a suitable consistence.Then pass the granulate through a rotating granulator equipped with thesuitable screen and transfer the granulate to the fluid bed drier tolower the residual moisture content under 3%.

After a new sieving on the dry, the granulate is added of 9.0 kg ofhydroxypropylcellulose (hydrophilic matrix forming material) and thesuitable amount of functional excipients (in particular,microcrystalline cellulose, lactose and silicon dioxide) and, after 15minutes of mixing, magnesium stearate in a suitable quantity to act aslubricant is added.

After a final blending, tablets of around 300 mg of unitary weight aregenerated.

The core are then subjected to be coated with a suspension obtainedintroducing into a stainless steel container 5.8 kg of Eudragit™(methacrylate copolymers), 0.6 kg of triethylcitrate and 3.0 kg of dyesand talc, using alcohol as solvent.

The mean dissolution percentage (as average of six or more tablets)obtained with this tablet formulation were around 10-20% at second hoursampling, in the range 25% to 65% at fourth hour and a dissolutiongreater than 80% was achieved at 8^(th) hour sampling.

Example B

Component mg/tablet Tablet Budesonide 9.0 Stearic Acid 10.0 Lecithin10.0 Microcristalline cellulose 156.0 Hydroxypropylcellulose 60.0Lactose monohydrate 50.0 Silicon dioxide 2.0 Magnesium stearate 3.0Coating materials Eudragit L100 14.0 Eudragit S100 12.0 Talc 7.9Titanium dioxiede 4.5 Triethylcitrate 1.6 Alcohol q.s.

According to the present invention, coated tablets individually weighingabout 220 mg are obtained.

The above described dissolution test is performed on the tablets ofExample B.

The results are the following (indicated as average value):

after 2 hours at pH 1 resistant (<5%) after 1 hour at pH 6.4 resistant(<5%) after 2 hours at pH 7.2 15% after 4 hours at pH 7.2 37% after 8hours at pH 7.2 91%

Example C

Budesonide (3.0 kg) is mixed with soybean Lecithin (5.0 kg) till anhomogeneous mixture is obtained. Then carnauba wax (2.0 kg) and stearicacid (2.0 kg) sieved through a fine screen are added. After mixing, thepowders are added with other functional excipients and kneaded with abinder solution obtained by dissolving medium viscositypolyvinylpirrolidone in water. After drying in a fluid bed and millingthroughout a suitable screen, hydroxypropylmethylcellulose (35.0 kg) andother excipients, including magnesium stearate as lubricant, in asuitable quantity are added and the mixture is blended till anhomogeneous powder dispersion is obtained.

The powder mixture is subjected to compression in a rotating tablettingmachine and the tablets so obtained are coated in a pan coat with agastroresistant composition containing Eudragit™, plasticizers, dyes andpigments.

According to the present example, coated tablets individually weighingaround 105 mg are obtained.

The results of the above described dissolution test are the following(indicated as average value of at least six tablets):

after 2 hours at pH 1 resistant (<5%) after 1 hour at pH 6.4 resistant(<5%) after 2 hours at pH 7.2  9% after 4 hours at pH 7.2 28% after 8hours at pH 7.2 86%

Example D

50 g of diethylene glycol monoethyl ether are homogeneously distributedon 500 g of microcrystalline cellulose; then 100 g of Budesonide areadded, mixing to complete homogenization. This mix is further added with400 g of Budesonide, then dispersed in a blender containing 100 g ofcarnauba wax and 100 g of stearic acid preheated at a temperature of 60[deg.] C. After kneading for 5 minutes, the mixture is cooled to roomtemperature and extruded in granules of size below 1 mm. A suitablemixer is loaded with the matrix granules prepared as above and thefollowing amounts of hydrophilic excipients: 1500 g of hydroxypropylmethylcellulose and 500 g of Policarbophil™ are added. The componentsare mixed until homogeneous dispersion of the matrices, then added with2450 g of microcrystalline cellulose, 400 g of lactose, 100 g ofcolloidal silica and 50 g of magnesium stearate. After further 5 minutemixing, the mix is tabletted to unitary weight of 250 mg/tablet.

Tablets are then subjected to coating using a suspension n containingpolyacrylate and poly methacrilate copolymers in addition to other dyes,plasticizers and colouring agents in solvent (ethylic alcohol).

The results of the dissolution test performed on these coated tabletsare the following (indicated as average value of at least six tablets):

after 2 hours at pH 1 resistant (<5%) after 1 hour at pH 6.4 resistant(<5%) after 2 hours at pH 7.2 11% after 4 hours at pH 7.2 32% after 8hours at pH 7.2 76%

1. (canceled)
 2. (canceled)
 3. A controlled release oral pharmaceuticalcomposition consisting essentially of: (1) a tableted core consisting ofa dispersion of ingredients, said ingredients comprising: a) budesonidein an amount to treat intestinal inflammation; b) magnesium stearate,stearic acid, or a mixture thereof; c) hydroxyalkyl cellulose; and d)optionally starch or a starch derivative; and (2) a coating on saidtableted core, said coating consisting essentially of a gastro-resistantfilm.
 4. The controlled release oral pharmaceutical compositionaccording to claim 3, wherein said ingredients further comprise lactose.5. The controlled release oral pharmaceutical composition according toclaim 3, wherein said ingredients comprise magnesium stearate.
 6. Thecontrolled release oral pharmaceutical composition according to claim 3,wherein said hydroxyalkyl cellulose is hydroxypropyl methylcellulose. 7.The controlled release oral pharmaceutical composition according toclaim 3, wherein said ingredients comprise starch.
 8. The controlledrelease oral pharmaceutical composition according to claim 7, whereinsaid ingredients comprise magnesium stearate.
 9. The controlled releaseoral pharmaceutical composition according to claim 8, wherein saidingredients further comprise lactose.
 10. The controlled release oralpharmaceutical composition according to claim 7, wherein saidhydroxyalkyl cellulose is hydroxypropyl methylcellulose.
 11. Thecontrolled release oral pharmaceutical composition according to claim 3,wherein said ingredients comprise a starch derivative and magnesiumstearate.
 12. The controlled release oral pharmaceutical compositionaccording to claim 11, wherein said hydroxyalkyl cellulose ishydroxypropyl methylcellulose.
 13. The controlled release oralpharmaceutical composition according to claim 3, wherein saidingredients comprise a starch derivative and magnesium stearate andfurther comprise lactose, lecithin, and microcrystalline cellulose. 14.The controlled release oral pharmaceutical composition according toclaim 13, wherein said hydroxyalkyl cellulose is hydroxypropylmethylcellulose.
 15. The controlled release oral pharmaceuticalcomposition according to claim 3, wherein said gastro-resistant filmcomprises methacrylic acid polymer.
 16. The controlled release oralpharmaceutical composition according to claim 4, wherein saidgastro-resistant film comprises methacrylic acid polymer.
 17. Thecontrolled release oral pharmaceutical composition according to claim 5,wherein said gastro-resistant film comprises methacrylic acid polymer.18. The controlled release oral pharmaceutical composition according toclaim 6, wherein said gastro-resistant film comprises methacrylic acidpolymer.
 19. The controlled release oral pharmaceutical compositionaccording to claim 7, wherein said gastro-resistant film comprisesmethacrylic acid polymer.
 20. The controlled release oral pharmaceuticalcomposition according to claim 8, wherein said gastro-resistant filmcomprises methacrylic acid polymer.
 21. The controlled release oralpharmaceutical composition according to claim 9, wherein saidgastro-resistant film comprises methacrylic acid polymer.
 22. Thecontrolled release oral pharmaceutical composition according to claim10, wherein said gastro-resistant film comprises methacrylic acidpolymer.
 23. The controlled release oral pharmaceutical compositionaccording to claim 11, wherein said gastro-resistant film comprisesmethacrylic acid polymer.
 24. The controlled release oral pharmaceuticalcomposition according to claim 12, wherein said gastro-resistant filmcomprises methacrylic acid polymer.
 25. The controlled release oralpharmaceutical composition according to claim 13, wherein saidgastro-resistant film comprises methacrylic acid polymer.
 26. Thecontrolled release oral pharmaceutical composition according to claim14, wherein said gastro-resistant film comprises methacrylic acidpolymer.
 27. A method for treating intestinal inflammatory disease in apatient, comprising administering to the patient the controlled releaseoral pharmaceutical composition according to claim
 3. 28. A method fortreating intestinal inflammatory disease in a patient, comprisingadministering to the patient the controlled release oral pharmaceuticalcomposition according to claim
 4. 29. A method for treating intestinalinflammatory disease in a patient, comprising administering to thepatient the controlled release oral pharmaceutical composition accordingto claim
 5. 30. A method for treating intestinal inflammatory disease ina patient, comprising administering to the patient the controlledrelease oral pharmaceutical composition according to claim
 7. 31. Amethod for treating intestinal inflammatory disease in a patient,comprising administering to the patient the controlled release oralpharmaceutical composition according to claim
 11. 32. A method fortreating intestinal inflammatory disease in a patient, comprisingadministering to the patient the controlled release oral pharmaceuticalcomposition according to claim 15.